The SOST gene encodes the protein sclerostin which is a 213 amino acids secreted glycoprotein. Sclerostin is a member of the super-family of cystine-knot containing factors. Sclerostin is related to the DAN/Cerberus protein family, which interferes directly with BMP signaling by inhibiting the binding of BMP to the receptors and thus the BMP signaling cascade (Avsian-Kretchmer, Mol Endocrinol 2004, 18(1):1-12).
Sclerostin mRNA expression is detected in adult humans predominantly in bone and kidney. Sclerostin protein is detectable predominantly in bone. Within bone its expression is restricted to the mature and terminally differentiated bone forming cells, the osteocytes.
Sclerostin is a potent negative regulator of bone formation in men and mice. Lack of SOST expression gives rise to sclerosteosis (Balemans et al. Hum Mol. Genet., 2001, 10(5):537-43; Brunkow et al. Am J Hum Genet, 2001, 68(3):577-89). Patients suffer from life-long bone overgrowth resulting in increased bone mineral density and strength. They display no other endocrinological abnormalities—all complications they experience during their life-time are related to the abnormal accumulation of bone. Heterozygous carriers for this recessive disorder also display increased bone mass (Gardner et al. J Clin Endocrinol Metab, 2005, 90(12):6392-5). This phenotype can be recapitulated in SOST deficient mice and its overexpression results in osteopenia. Furthermore Van Buchem disease [MIM 239100]—a phenotypic copy of sclerosteosis—is caused by SOST misregulation due to the genomic deletion of a long-range bone enhancer (Balemans et al. J Med Gene, 2002, 39(2):91-7; Loots et al., Genome Res, 2005, 15(7):928-35). Finally, SOST is down-regulated by parathyroid hormone—a clinically validated bone forming principle—during bone formation suggesting that part of the anabolic action of PTH might be mediated via SOST (Keller and Kneissel Bone, 2005, 37(2):148-58).
Sclerostin binds BMPs (bone morphogenic proteins) and can act as a BMP antagonist in vitro (Winkler et al. EMBO J., 2003, 22(23):6267-76). Sclerostin also acts as a negative regulator of canonical Wnt signaling, either directly by binding to LRP5/LRP6 (Li et al. J Biol. Chem., 2005, 20; 280(20); Semenov, J Biol. Chem. 2006 Oct. 19; van Bezooijen et al. J Bone Miner Res, 2006, October 10), or indirectly (Winkler et al. J Biol. Chem., 2005, 28; 280(4):2498-502).
Lack of sclerostin expression results in high bone formation, while bone resorption is undisturbed (Sclerosteosis, Van Buchem disease) (Balemans et al. 2001; Brunkow et al. Am J Hum Genet, 2001, 68(3):577-89, Balemans et al. 2006; Loots et al., Genome Res, 2005, 15(7):928-35).
Few of the presently available treatments for skeletal disorders can increase the bone density of adults, and most of the presently available treatments work primarily by inhibiting further bone resorption rather than stimulating new bone formation.
One example of a medicament used for treating bone loss is estrogen. However, it is not clear whether or not estrogen has any beneficial long term effects. Furthermore, estrogen may carry the risk of increasing the prevalence of various types of tumors, such as breast and endometrial cancer. Other current therapeutic approaches to osteoporosis include bisphosphonates (e.g., Fosamax™, Actonel™, Bonviva™, Zometa™, olpadronate, neridronate, skelid, bonefos), parathyroid hormone, calcilytics, calcimimetics (e.g., cinacalcet), statins, anabolic steroids, lanthanum and strontium salts, and sodium fluoride. Such therapeutics, however, are often associated with undesirable side effects.